Optimal Design And In Vitro-in Vivo Evaluation Of Thermosensitive Nanoemulsion Hydrogel For Sustained-release Of Praziquantel

Objective: This work aimed to design an alternative sustained-release thermosensitive praziquantel-loaded nanoemulsion(PZQ-NE)hydrogel to solve the problems,such as the poor solubility and bioavailability of PZQ,and the large dosage and frenquent use of the existing preperations,for better schistosomiasis treatment.Methods: Solubility tests were applied to screen optimal oils and surfactants.Pseudo-ternary phase diagrams were constructed to select co-surfactants and the mass ratio of surfactant and co-surfactant(Km)of PZQ-NE.Nanoemulsion hydrogels(NE/CS/?-GP/HMPC)were preparared by dispersing PZQ-NE into hydrogel solution.The NE/CS/?-GP/HMPC hydrogels were characterized for gelling time,surface exudates,rheological properties and in vitro drug release.Formulation optimization of NE/CS/?-GP/HMPC hydrogel was conducted by Box-Behnken experimental design combined with response surface methodology.In vitro cytotoxicity of hydrogel was studied by MTT method.The sustained-release property of PZQ in NE and optimized hydrogel was evaluated by pharmacokinetic study in rabbits.Results: The formulation of PZQ-NE consisted of mass ratio of 12.5 % capryol 90 containing PZQ(160 mg/g),40 % cremophor RH 40/tween 20 and transcutol HP(S/CoS = 2:1),47.5 % deionized water,with a small mean diameter of 20.5 ± 0.13 nm.PZQ-NE showed better thermostability and could be evenly dispersed in hydrogels.The results of characteristic investigation experiments demonstrated that the addition of HPMC could effectively reduce the amount of PZQ in the exudates of hydrogel surface and did not extend the gelling time.PZQ releasing from NE/CS/?-GP/HMPC hydrogels fitted to Higuchi model and governed by diffusion.Rheological investigation evidenced that the themosensitive gelation of different hydrogel systems and their gel-like character at 37 ?.The optimized hydrogel formulation consisted of HPMC solution(103.69 mg/g),3.03 %(w/v)chitosan and 14.1 %(w/v)?-GP showed no cytotoxicity when the addition of NE was no more than 100 mg/g.Pharmacokinetic parameters indicated that NE/CS/?-GP/HMPC hydrogel can significantly slow down drug elimination,prolong mean residence time and improve bioavailability of PZQ in rabbits.Conclusions: NE/CS/?-GP/HMPC hydrogel could not only successfully improve the insolubility and bioavailability of PZQ,but also showed no cytotoxicity.Due to the applicable physicochemical property which could meet the requirement of clinical practice,it could be an alternative antischistosomal drug delivery system with improved therapeutic effect.